The present invention regards microcapsules where a water phase is in inside the core together with biologically active ingredient(s), simplified process of microencapsulation and mixed formulations (capsule suspension plus suspension in oil, capsule suspension plus suspension concentrate, etc) and uses thereof. Further, here is described in full for the first time a usable agricultural formulation type that we called Capsule Mixed Suspension (proposed CX for a new two-letter code of international classification of formulations) characterized in that the formulation contains: i) a water or oil continuous outer phase ii) microcapsules containing an oily core with oil-soluble active ingredients and iii) microcapsules containing a watery core with water-soluble active ingredients iv) suitable coformulants, in particular surface active compounds.
The unitary concept of this invention is the reverse microencapsulation of water soluble (or dispersible) materials—active ingredients or a.i.—.
The technique of microencapsulation is well known in many fields. One field of special interest for the inventors is agrochemistry (any type of chemical compounds that are used in agriculture to improve the benefits of the farmer, including herbicides, fungicides, insecticides, raticides, semiochemicals, viricides, molusquicides, etc). However fields as cosmetics, medicine, pharmaceutics, etc., may take profit of the same microcapsule's and processes. For simplicity we will focus on agricultural uses.
The a.i. referred herein is in any of its forms, as long as it achieves a biologically technical effect, Traditionally the a.i. (in short, a.i., the use of the term “a.i.” is used in plural, unless it is explicitly understood that is singular by the context) is referred as to the molecule (or moiety of the molecule) with herbicide, insecticide, attractant, etc. activity. For example, in an herbicide composition, the a.i. would be the molecule having herbicidal activity; in a cosmetic preparation, a fungicide that is part of the formulation and is inside the microcapsules would be an a.i., although such formulation may not be directed primarily to have antifungal effects (maybe is used for anti-wrinkle effect). The a.i. can be considered as well a safener or penetrator (e.g., fatty alcohol ethoxylates for “fop” herbicides) in a herbicidal composition or a penetrator enhancer for fungicides or herbicides (e.g. N-octyl-2-pyrrolidone), or a synergistic compound (e.g., a photosynthesis inhibitor that acts synergistically with the herbicide “main” a.i.; also a synergist in the case of insecticides of the pyrethroid type (e.g., pyperonyl butoxide). In other words, anything that has any type of biological activity either in its own or combined with another compounds, is to be understood as a.i. in the present invention. What would not be a.i. are, for example clays, buffers, surface active compounds in so far they do not affect significantly the biological effect of the a.i. and are present in the formulation as technological aids for the purpose of achieving usable formulation (e.g., stable and perfectly dispersable in the spray tank), etc.
The vast majority of known (true—it is said, those that have a wall that makes a physical separation of the a.i. from the continuous phase, to the contrary of those non-true “microcapsules” made by matrix encapsulation) microcapsules in the agrochemical field have in their core (discontinuous phase) a water-insoluble phase, it is said, the content of the microcapsule is oily, unpolar, substantially insoluble in water, and the microcapsules are dispersed in water (continuous phase). Inside the core may be solids or dispersed materials. Most of the prior art discloses microcapsules where the oily a.i.(s) is inside the microcapsule. We refer to it as normal microencapsulation or normal phase microencapsulation (NPμ in short).
However, there are many limitations as to form microcapsules where the continuous media is oily and the core contains water with water-soluble a.i. This is usually referred as reverse phase microencapsulation (RPμ in short). Patents dealing with RPμ, but providing rather different solutions are U.S. Pat. No. 6,531,160 (reactive wall forming materials not suitable for the purposes of this invention), U.S. Pat. No. 6,534,094 (biodegradable polymer, undesired for our addressed problems, since we need a wall strong to weathering conditions) or U.S. Pat. No. 6,572,894 (biodegradable wall as well).
The prior art shows an overwhelming presence of NPμ patents and scientific papers over that of RPμ. The state of the art presents a very restricted ways as how to produce RPμ. The use of oil soluble isocyanates or urea/melamine formaldehyde resins is the conventional way of performing NPμ. In the prior art, for achieving RPμ, the chosen wall forming materials must be in the water phase—or at least part of them—at the beginning of the process, therefore leading to undesired degradation of some a.i. due to the reactive nature of these water-soluble wall forming materials (e.g., polyols, wherein the hydroxyl group is free to react), difficulting the full reaction of wall forming materials and leading to microcapsules of 30-100 μm, bigger and more inhomogeneous than those obtained in this invention (see Example 10, CEI).
After producing the RPμ, the microcapsules must be mixed with the appropriate coformulants in order to obtain a functionally usable form of the microcapsules (e.g., addition of dispersants, wetters, skin UV-protectors . . . ). Normally the NPμ microcapsules are formulated in a water phase (e.g., capsule suspensions for agriculture) or after a drying process yielding water dispersable granules. Therefore, a need of different coformulants for the RPμ process and for the “second” process of formulation may cause logistic problems, especially to small companies wherein the availability of highly special chemicals (coformulants for NPμ or RPμ) is limited.
One problem addressed in this invention is to obtain in the same commercial formulation NPμ and RPμ. Note that not even one product in the market has ever had this particular feature (double-beneficial encapsulation of water and oil soluble a.i.).
One of the main problems to be solved when performing a microencapsulation (if not the most important problem) is to choose the right wall forming materials in order that they:
do not react with the a.i. or coformulants, either by the presence in the same initial water phase or by its lack of reactivity towards the chosen a.i.
do polymerize in a controlled way
do not leave unreacted compounds or toxic compounds after polymerization
do form a polymer with the appropriate thickness, porosity and hydrophobicity to allow the desired controlled release of the a.i.
do permit that the size of the microcapsules is sufficient small for a correct functionality
the distribution of the size to be uniform
This is achieved in this invention by a purposive selection of wall forming materials. The selection of the wall forming materials according this invention has been done with due account of preserving all the needs state above and, moreover, are appropriate for the much less usual reverse phase microencapsulation. Our selected wall forming materials allow not only such needs but also allow to microencapsulate a.i. in a high loads without the use of PVP polymers, also, a very homogeneous particle size distribution, and a very low amount of unencapsulated material. The use of glycoluril resins makes the process much less dangerous in terms of human toxicology in front of prior art use of monomer isocyanates (with high toxic profile and volatility). The use of glycoluril resins also makes the capsules more elastic and resistant to rupture by stresses during the production and afterwards (e.g., filling machines).
The problems addressed by the invention are several, although the invention can be formulated as to solve other problems as well, implicitly existing in the RPμ process.
The first problem is to find a reliably, simple and effective process of RPμ having microcapsules with small and homogeneous particle size and appropriate porosity. Other problem addressed is to be able to simplify the process of formulating for agriculture the RPμ product in such a way the need of different types of raw materials for the formulation plant is reduced to a minimum, for logistical and economic reasons. Also we address the need of avoiding or reduce to a minimum the degradation of the a.i. during the process (or even during storage) due to undesired side reactions. Also, we look for the combination of labile water—and/or oil-soluble a.i. in the same formulation. Obtaining a dry and stable and functional formulation of microcapsules made by RPμ, eventually with oil soluble a.i. incorporated in the dry formulation, is also one of our targets. Here is presented for the first time fully functional agricultural formulations wherein the two types of microcapsules are combined (the CX). There is no commercial product containing combined capsule suspensions (namely, NPμ and RPμ). The prior art shows enabling disclosures of formulations of microcapsules containing water phase in the core, or, always alternatively, oil phase in the core, but never before an enabling disclosure of a formulation containing simultaneously two types of microcapsules with a watery-core and an oily-core. It is highly surprising that this need has been never solved during more than 40 years after the first microencapsulation processes appeared and the increased efforts in the Agro industry to develop new formulations (reducing the investment in searching new molecules). It is uncontestable that this invention provides a big step forward in the field of formulation, at the view to the increased patents of the field of formulation and microencapsulation in the last years, and the fact that no patent addresses this problem of microencapsulating oil and water soluble a.i. with two different techniques and combine the final products.
The invention solves these problems in the following way:
Providing a new process of RPμ with the use of determined wall forming materials, coformulants—those disclosed herein may be interchangeable with similar ones as far as the functionality is the same (e.g., with the same HLB and solubility properties) and preferably the molecular structure is similar—, and selective ratios, conditions of reaction and treatment (formulation) of the solution microcapsules formed.
Simplifying the process of RPμ in such a way that the same coformulants that are used in the step of formulation (same coformulants for different types of finished formulations). We refer to Example 1 to understand better this solution, where a RPμ Capsule Suspension (CS) formulation is formulated with the same coformulants as a combined CS-EC formulation (Capsule Suspension+Emulsion Concentrate).
Obtaining a very reliable process of RPμ with a sharp distribution of the microcapsule's size without the need of use prior art coformulants deemed essential till now for RPμ (e.g., polymers of the type of polyvinylpyrrolidone—PVP—) and without the need of adding any wall forming material in the water phase initially prepared, by means of choosing oil soluble wall forming materials and avoiding the contact of any water soluble wall-forming material (that may be present) until at least the emulsification step, wherein the contact of water soluble ingredients is reduced to a minimum (seconds or minutes at discrete intervals under agitation).
Microencapsulating by RPμ the water soluble (or dispersible) a.i. and having the oil soluble ingredient dispersed or dissolved in the continuous oil phase, with the processes already envisaged above and later mixing with NPμ.
Drying the formed microcapsules, both with a water soluble a.i. as the only a.i.; and also combination of water soluble a.i. with oil-soluble a.i., the latter being outside of the microcapsules. It cannot be assessed beforehand if our RPμ would be stress-resistant to spray drying.
Formulating the RPμ in such a way that can be incorporated with other formulations containing NPμ, providing a completely new approach in the agrochemistry field of formulations—there is not even an international code (e.g., used by the FAO or by the BCPC) for the type of formulations CX—.
We take a closer view of the prior art at the view of the problems cited.
U.S. Pat. No. 3,464,926 and U.S. Pat. No. 3,577,515 (Van de Gaer et al., Pennwalt Corporation) are pioneer inventions in the field of microencapsulation. As shown in FIGS. 1 and 2 of U.S. Pat. No. 3,464,926 and description thereof, the process is far complicated using flows and industrially complicated paths for the reactants to travel, economically very costly nowadays to bring into practice. Further, that patent refers only to microencapsulation of pesticides (diazinon and malathion) in “normal” phase, namely, oil in water, where the oil-soluble insecticide remains inside the microcapsule.
The RPμ is described in U.S. Pat. No. 3,577,515 Example 15, with the use of petroleum ether, carbon tetrachloride, talc, tetraethylene pentamine, calcium hydroxide, water, and dimer acid chloride, being the wall formed by the reaction of dimer acid chloride with tetraethylene pentamine. This (reactants, microcapsules formed, and process) process is rather different than the one described in the present invention, where, for example, we make no use of acid chlorides (highly reactive and likely to degradate a.i. to react to form the wall. No mention of the use of the RPμ for any agrochemical use is suggested in the case of water in oil microencapsulation, either the recommended sizes for a good performance in the final application in the field of such microcapsules or release rate characteristics.
The inventors have observed that, contrary to what is described in the closest prior art U.S. Pat. No. 4,524,783, where to form to polyurea wall to microencapsulate the water soluble compounds they use necessarily polyols [Examples 2, 3, 4, 6, 7, 8, 9 and 10] or polyamines [Examples 1 and 5] in the water phase), there is no need of using any amine or any alcohol or any further compound in the water phase to achieve a the RPμ according to the present invention. Having wall forming materials in the water phase provokes eventually undesired side reactions with the a.i. (this fact is so obvious for a skilled in chemistry that we do not provide more information on this regard). The present invention solves this problem “isolating” the a.i. in the water phase. According to the present invention, the microencapsulation may be carried out with a water phase that only contains the water soluble compounds(s) (a.i.) and water. This suppressive possibility of the removal of any additional compound in the water phase is beneficial for the stability of the water soluble compound(s) to microencapsulate, since the reactions of decomposition or just any kind of interference, are avoided by virtue of “isolating” the water soluble-a.i.(s) in a phase, leaving all the rest of the compounds in the other phase (oil phase).
One of the problems addressed in the present invention is to provide a water phase free from wall forming materials (if needed so) that may interact with the water soluble a.i.(s) to microencapsulate. All prior art cited above use part of the wall forming material to be in the oil phase, U.S. Pat. No. 4,534,783 makes use of diols in the water phase to react with the adipyl chloride (in example 4) or with the 1,6-Hexamethylenediisocyanate in example 3, or the amines in example 5, etc. U.S. Pat. No. 6,113,935 uses in wall forming materials in the water phase; in Table 1 (examples 2 to 8) the prepolymeric water forming material in the water phase is WS-351-380, or even urea/formaldehyde in the example 1.
U.S. Pat. No. 6,359,031 (Lykke et al.) performs a RPμ process by virtue of using carboxy-functional polymers to associate with amine functional reactive monomers in order to avoid that the non-protected (by carboxy groups) polymers are dispersed in the oil phase—remarking our addressed problem of undesired side reactions due to reactivity of wall-forming materials—. This solution is far complicated to perform, due to the cost of functionalizing with carboxy groups the water soluble polymers (implying lack of commercial sources or high prices of proposed polymers). This solution is appropriate for high-priced final microcapsules, as those described therein for enzymes, but such solution, as of today, is not viable for industrial application in the field of agrochemistry. Moreover, the extremely complicated modification of the polymers in order to achieve RPμ, when compared to this invention, makes more suppressive and inventive the easy solution proposed in the present invention. Also exists the possibility that these carboxy-protected polymers (the carboxy group or reduced aldehydes/ketones or alcohols) react with the water soluble a.i.(s).
U.S. Pat. No. 6,113,935 (Rodson and Scher, Zeneca Ltd.), published in 2000, still addresses the microencapsulation providing a water phase containing the reactive wall forming materials. This approach is preferentially avoided in the present invention, to avoid any side reaction in between the products to microencapsulate and for the first time here allowing a reverse microencapsulation with the use of only oil soluble wall forming materials. The presence of urea or melamine formaldehyde polymers in the water phase makes more difficult the completion till the end of the wall forming reaction, as well explained in U.S. Pat. No. 6,113,935 A1, col. 5: “As the polymer wall becomes more rigid, contact between the active groups on the [water-soluble] prepolymer becomes increasingly more difficult.” This chemical scenario is completely reversed in our case. Since the wall forming materials are in the oil phase, the increased thickness of the wall will not prevent that the rest of the material self-polymerizes. When in U.S. Pat. No. 6,113,935 is said that the polymerization reaction is “self-terminating” is not due to a perfect availability of wall forming materials to react completely (it is not desirable to have rests of toxic unreacted wall forming materials in the final formulation), rather to the impossibility due to the growth of the wall thickness of complete reaction of the wall forming materials. Therefore, in U.S. Pat. No. 6,113,935, it is said “the reaction is self-terminating and is generally allowed to run to completion”, provided this is interpreted in the light of the previous sentence where it is explained that this completion is due to the difficulty of the active groups of the water soluble prepolymer to really react completely. In our microencapsulation process, by virtue of the presence of the wall forming materials in the oil phase, there is indeed a completion of the reaction thanks to the absolutely complete reaction of the wall-forming materials (to the difference of U.S. Pat. No. 6,113,935, where the “completion” or “finishing” is due to unavailability to react more than the limit given by the wall thickness). Moreover, U.S. Pat. No. 6,113,935 system does not provide a solution to use the same process/components (of, e.g., Adjustment Mixtures A and B from our Example 1) for producing agrochemical formulations that may later be transformed easily in a combined formulation, as the solution offered in the present invention. No hint is provided as to formulate RPμ with NPμ.
It must be acknowledged that from a scientific point of view, the specialized literature is a source of guarantied knowledge for the state of the art, in between other things, because are peer reviewed publications, the prestige and the scientific correctness of the writer is in play and this is the way, how the scientist and technicians obtain fairly “trusted” information sources. We find in the book “Chemistry of Crop Protection” (Edited by Voss and Ramos, from the recognized Publisher Wiley-VCH, ISBN 3-527-30540-8) that the solution proposed by the inventors of the present patent goes against any expectation for the skilled in the art; namely, our proposal of using the wall forming materials only in the oil phase is disregarded as possible by the recognized microencapsulation expert George B. Beestman—inventor of one of the few RPμ and process, U.S. Pat. No. 4,534,783—, in pg. 273 of that book: “To prepare the reverse phase W/O (Water-in-Oil) emulsions care must be taken to select monomers that will remain in the dispersed water droplet during the emulsion stage. If the monomers diffuse from suspended droplets into the continuous phase polymerization will happen throughout the emulsion and not at the interface as intended. No microcapsules will be formed”. He insists later in the same paragraph that in a process where amines participate, the microcapsules would have not been produced. The relatively new book (edited in 2003), used as standard reference in this field, does not give any hint into initiating the emulsification process without any compound in the water phase, lesser to provide the catalyst (in our case eventually a cycled azo compound) after emulsification has began, rather teaches away from the solution proposed. This inventiveness shown in the present application must be taken into account when considering that the closest prior art available is a patent of the author that teaches away from our solution proposed (Beestman shows a RPμ for water soluble agrochemicals). In the same chapter of Beestman, a mention of in-situ polymerization is made, but this time no reference of a possible formation of a RPμ is made using this type of polymerization (in fact, the only envisaged methods in the patent literature of performing a RPμ are those using the wall forming material either only in the water phase or in both oil and water phases, but not only in the oil phase as addressed in this invention in its preferred embodiment).
Note that according the invention, it is not addressed only that the water phase contains no wall forming material, rather, that in our aim to provide a simplified process of production of reverse phase microcapsules for further addition of other components or transformations in the formulation types—e.g. from a Capsule Suspension (CS) to a CS plus suspension concentrate (SC)—. Although we have found that one of the preferred embodiments is highly surprising over the state of the art, in the sense of the placing wall forming materials in the oil phase, nothing prevents the skilled in the art to use other features of this invention with traditional RPμ with wall forming material in the oil phase, as long as other benefits of this invention are achieved (e.g., combined RPμ and NPμ (CX formulation)). Then, the disclosure of this invention also embraces embodiments that have wall-forming materials in both phases, as a less attractive alternative, but possible. In this case it is needed that any material present in the water phase is inert with regard the a.i. and other components of the (initial) water phase. The term “inert” is well defined and clear in this invention: the water-soluble wall forming materials must not react, in the presence of water, and in the same proportions that are used in the water phase preparation of the process described herein, with the water-soluble a.i.(s) chosen, that are in the water phase.
These notes are needed to emphasize that the present invention solves the main problem of finding an improved process of microencapsulation of water soluble or dispersible a.i., and the partial problems of facilitating logistical needs and combinations of the microcapsules formed. Each of these partial problems has its own solution that may be used independently, with the common inventive concept of new RPμ applications. The same applies to the other partial problems mentioned above.
The invention comprises—when isolating its application in agrochemistry—the combination in a single formulation, of at least a microencapsulated water soluble agrochemical (preferably glyphosate and/or sulfosate and/or glufosinate) combined with an oil soluble insecticide outside the microcapsules (preferably sulfonylureas and/or sulfonamides) or in normal phase microcapsules, in such a way that all the a.i. remain stable, and optionally drying the resulting combination to obtain water dispersable granules containing RPμ and NPμ encapsulated (also non-encapsulated) sulfonylureas. Some preferred embodiments including sulfonylureas emanates due to the well-known instability of sulfonamides, and the wide use of glyphosate, sulfosate and glufosinate. Surprisingly, the inventors have realized that the process to microencapsulate water soluble herbicides herein disclosed, may be continued with the addition in the oil phase of sulfonylureas without any detriment to the functionality of the first microencapsulated water-soluble agrochemical or the subsequently added oil soluble material. Therefore the invention provides using the same process, either RPμ-water-soluble agrochemical (e.g. glyphosate) or, if desired, RPμ-water-soluble agrochemical plus oil soluble agrochemical (free or NP-microencapsulated).
It must be noted that the state of the art processes for NPμ, allow to have dry microcapsules containing oily agrochemicals in the core of microcapsules. These microcapsules can be added (dispersed) in the continuous phase of a RPμ formulation, in such a way at the end we have a formulation with water-soluble ingredients microencapsulated but also with oil-soluble ingredients microencapsulated. The dispersion in oil of such water-dried microcapsules can be done using dispersants of the type sodium alkyl naphthalene sulfonate, cresolformadehyde condensation products, EO/PO block copolymers or metal salts of fatty acid methyl taurides. As wetters for good dispersibility and suspensibility, we propose isotridecyl alcohol ethoxylate, sodium lauryl sulphate and metal salts of alkylsulfosuccinate, like sodium dioctylsulfosuccinate.
It is a question of obviousness that, in principle, any water soluble stable small organic molecule (e.g., agrochemicals, many medicines, alkaloids, oligopeptides) may be submitted to our RPμ and also that any oil soluble stable small organic molecule (e.g., agrochemicals, many medicines) may be added to the oil outer phase.
It is also a question of common knowledge for the skilled in the art which agrochemicals are not comprised in the scope in the patent, namely, those which for whatever reason would not be able to be used according the present invention: for example, an inorganic water or oil insoluble fertilizer could not fall in the scope of the invention if there is no reasonable mean to disperse it in the water or the oil phase; either any a.i. that would decompose by thermal degradation at the temperatures set out in the present invention. Namely, we claim that the invention is feasible in all the range of a.i. except those that can obviously not be submitted to our process. For the selection of the a.i., no undue burden is left to the skilled in the art, rather, only his/her normal knowledge in the area of microencapsulation and chemistry.